Renal pharmacology - Pharmacology for Medical Graduates, 4th Updated Edition

CO ₂ and H ₂ O from the tubular lumen diffuse into tubular cell where H ₂ CO ₃ is formed under the influence of carbonic anhydrase ( Fig. 4.2 ). Carbonic acid (H ₂ CO ₃ ) dissociates into H ⁺ and HCO ₃ ⁻ . The bicarbonate ions are transported into the interstitium. The H ⁺ ions exchange with luminal Na ⁺ (Na ⁺ –H ⁺ antiporter). In the lumen, H ⁺ ions combine with the filtered HCO ₃ ⁻ to form H ₂ CO ₃ . The H ₂ CO ₃ dissociates into CO ₂ and H ₂ O with the help of carbonic anhydrase, which is present near the brush border. The main site of action of acetazolamide is proximal tubule (site 1); it also acts in the CD. Acetazolamide, by inhibiting carbonic anhydrase enzyme, prevents the formation of H ⁺ ions. Thus, Na ⁺ –H ⁺ exchange is prevented. Na ⁺ is excreted along with HCO ₃ ⁻ in urine.

Mechanism of action of carbonic anhydrase (CA) inhibitors.

In the DCT, increased Na ⁺ –K ⁺ exchange leads to loss of K ⁺ . The net effect is loss of Na ⁺ , K ⁺ and HCO ₃ ⁻ in urine resulting in alkaline urine.

Acetazolamide is not used as diuretic because of its low efficacy. It is used in the following:

• 1.

  Glaucoma: Carbonic anhydrase inhibitors decrease intraocular pressure (IOP) by reducing the formation of aqueous humour. Acetazolamide is used in acute congestive glaucoma by oral and i.v. routes. Topical carbonic anhydrase inhibitors (dorzolamide and brinzolamide) are used in chronic simple glaucoma (see p. 58).

• 2.

  To alkalinize urine in acidic drug poisoning.

• 3.

  Acute mountain sickness: Acetazolamide can be used both for symptomatic relief and prophylaxis of acute mountain sickness. It is better to administer it prophylactically. The beneficial effect may be due to a decrease in pH and formation of cerebrospinal fluid.

• 4.

  Miscellaneous: As an adjuvant in familial periodic paralysis – benefit results from lowering of pH.

These include hypersensitivity reactions (skin rashes, fever, nephritis, etc.), drowsiness, paraesthesia, hypokalaemia, metabolic acidosis, headache and renal stones.

• 1.

  Liver disease: Hepatic coma may be precipitated in patients with cirrhosis due to decreased excretion of NH ₃ in alkaline urine.

• 2.

  Chronic obstructive pulmonary disease (COPD): Worsening of metabolic acidosis is seen in patients with COPD.

Osmotic diuretics draw water from tissues by osmotic action. This results in increased excretion of water and electrolytes. Their site of action is in the loop of Henle and proximal tubule.

• 1.

  Mannitol is used to reduce the elevated intracranial tension (ICT) following head injury or tumour. It draws fluid from the brain into the circulation by osmotic effect, thus lowering ICT.

• 2.

  Mannitol 20% (i.v.), glycerol 50% (oral) and isosorbide (oral) are used to reduce the elevated IOP in acute congestive glaucoma. They draw fluid from the eye, by osmotic effect, into blood – IOP is decreased.

• 3.

  Mannitol is used to prevent acute renal shutdown in shock, cardiovascular surgery, haemolytic transfusion reactions, etc.

• 4.

  Mannitol is useful to maintain the osmolality of ECF after dialysis.

• 1.

  Too rapid and too much quantity of i.v. mannitol can cause marked expansion of ECF volume which can lead to pulmonary oedema.

• 2.

  Headache, nausea and vomiting may occur.

• 3.

  Glycerol can cause hyperglycaemia.

Mannitol is contraindicated in congestive cardiac failure (CCF) and pulmonary oedema because it expands ECF volume by increasing the osmolality of extracellular compartment and increases the load on heart, thus, aggravating the above condition. Other contraindications are chronic oedema, anuric renal disease, active intracranial bleeding and acute tubular necrosis.

Site of action is the thick ascending limb of loop of Henle (site 2). Loop diuretics bind to luminal side of Na ⁺ –K ⁺ –2Cl ⁻ cotransporter and block its function. There is an increased excretion of Na ⁺ and Cl ⁻ in urine. The tubular fluid reaching DCT contains large amount of Na ⁺ . Hence, more Na ⁺ exchanges with K ⁺ , leading to K ⁺ loss. Furosemide has weak carbonic anhydrase–inhibiting activity, hence, increases the excretion of HCO ₃ ⁻ . Loop diuretics also increase the excretion of Ca ²⁺ and Mg ²⁺ .

Na ⁺ –K ⁺ –2Cl ⁻ cotransport system in thick ascending limb and the mechanism of action of loop diuretics.

Loop diuretics are called high-ceiling diuretics because they are highly efficacious – have maximal Na ⁺ excreting capacity when compared to thiazides and potassium-sparing diuretics.

The loop diuretics are rapidly absorbed through the gastrointestinal tract. Furosemide and bumetanide are administered by oral, i.v. and i.m. routes. Torsemide is given orally and intramuscularly. Furosemide has a rapid onset of action within 2–5 minutes of i.v.; 10–20 minutes after i.m. and 30–40 minutes after oral administration. The duration of action of furosemide is short (2–4 hours).

• ■

  Can be administered orally and parenterally.

• ■

  Are more potent than furosemide.

• ■

  Have better oral bioavailability than furosemide.

• ■

  Torsemide: Longer half-life than others.

• 1.

  During the initial stages of renal and cardiac oedema, loop diuretics are preferred. They are also useful in hepatic oedema – vigorous diuresis should be avoided to prevent hepatic coma.

• 2.

  Intravenous furosemide, along with isotonic saline (to prevent volume depletion), is used in hypercalcaemia as it promotes the excretion of Ca ²⁺ in urine.

• 3.

  Acute pulmonary oedema – loop diuretics act in the following way:

  

• 4.

  Loop diuretics may be used in cerebral oedema but i.v. mannitol is the preferred drug.

• 5.

  Hypertension: Loop diuretics can be used in hypertension associated with CCF/renal failure and in hypertensive emergencies. Furosemide is not preferred in uncomplicated primary hypertension because of its short duration of action.

• 6.

  To prevent volume overload, furosemide is administered during blood transfusion.

• 1.

  Electrolyte disturbances are the common adverse effects seen with loop diuretics. They are as follows:

  • (a)

    Hypokalaemia: It is the most important adverse effect. It can cause fatigue, muscular weakness and cardiac arrhythmias. Hypokalaemia can be prevented by using a combination of loop diuretic with potassium-sparing diuretic. It can be treated by K ⁺ supplementation.

  • (b)

    Hyponatraemia: Loop diuretics can cause depletion of sodium from the body.

  • (c)

    Hypocalcaemia and hypomagnesaemia: These are due to the increased urinary excretion of Ca ²⁺ and Mg ²⁺ , respectively. Hypomagnesaemia can predispose to cardiac arrhythmias.

• 2.

  The metabolic disturbances include:

  • (a)

    Hyperglycaemia: This can occur due to decreased insulin secretion.

  • (b)

    Hyperuricaemia: These drugs decrease the renal excretion of uric acid and may precipitate attack of gout.

  • (c)

    Hyperlipidaemia: They increase plasma triglycerides and LDL cholesterol levels.

• 3.

  Ototoxicity manifests as deafness, vertigo and tinnitus and is due to damage to hair cells in inner ear. The symptoms are usually reversible on stoppage of therapy. The risk of ototoxicity is increased in patients with renal impairment and in those receiving other ototoxic drugs like cyclosporine and aminoglycosides.

• 4.

  Hypersensitivity: Skin rashes, eosinophilia, photosensitivity, etc. may occur.

• 1.

  Furosemide/thiazides × digoxin: These diuretics cause hypokalaemia which increases the binding of digoxin to Na ⁺ -K ⁺ -ATPase leading to digoxin toxicity.

• 2.

  Furosemide × aminoglycosides: Both are ototoxic drugs and cause enhanced toxicity when used together.

• 3.

  Furosemide × nonsteroidal anti-inflammatory drugs (NSAIDs): NSAIDs inhibit PG synthesis and block prostaglandin-mediated haemodynamic changes of loop diuretics. Chronic use of NSAIDs leads to Na ⁺ and H ₂ O retention and diminish the antihypertensive effect of loop diuretics/thiazides.

• 4.

  Furosemide/thiazides × lithium: Diuretics cause hyponatraemia resulting in compensatory increase in reabsorption of sodium and lithium in the PCT leading to lithium toxicity.

• 5.

  Furosemide/chlorthalidone × amiloride: Furosemide/chlorthalidone causes hypokalaemia, whereas amiloride conserves potassium. The combination of these diuretics does not alter plasma potassium levels; also improves diuretic response – synergistic effect.

Thiazides inhibit Na ⁺ –Cl ⁻ symport in early distal tubule (site 3) and increase Na ⁺ and Cl ⁻ excretion ( Fig. 4.4 ). There is increased delivery of Na ⁺ to late distal tubule. Hence, there is increased exchange of Na ⁺ –K ⁺ which results in K ⁺ loss. Some of the thiazides also have weak carbonic anhydrase inhibitory action and increase HCO ₃ ⁻ loss. Therefore, there is a net loss of Na ⁺ , K ⁺ , Cl ⁻ , HCO ₃ ⁻ in urine. Unlike loop diuretics, thiazides decrease Ca ²⁺ excretion.

NaCl reabsorption in early distal tubule and mechanism of action of thiazides. (Source: Adapted from Alfred Gilman Sr. and Louis S. Goodman: Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 13th edition, McGraw Hill, 2018.)

Thiazides are administered orally. They have long duration of action and are excreted in urine.

• 1.

  Hypertension: Thiazides are used in the treatment of essential hypertension (see p. 104).

• 2.

  Oedema: Thiazides are used in combination with loop diuretics in severe CHF. They are not very effective in hepatic oedema. Most thiazides, except metolazone, are not effective when glomerular filtration rate (GFR) is low.

• 3.

  Hypercalciuria: Thiazides are used in calcium nephrolithiasis as they reduce the urinary excretion of calcium.

• 4.

  Diabetes insipidus (DI) (see p. 163).

• 1.

  Thiazides cause electrolyte disturbances which include hypokalaemia, hyponatraemia, hypomagnesaemia and hypercalcaemia.

  • (a)

    Hypokalaemia is more common with thiazides than loop diuretics because of their long duration of action.

  • (b)

    Hypercalcaemia is due to decreased urinary excretion of Ca ²⁺ .

• 2.

  The metabolic disturbances are similar to that of loop diuretics – hyperglycaemia, hyperlipidaemia and hyperuricaemia.

• 3.

  They may cause impotence; hence, thiazides are not the preferred antihypertensives in young males.

• 4.

  Others: Skin rashes, photosensitivity, gastrointestinal disturbances like nausea, vomiting and diarrhoea can occur. Diuretics should be avoided in pregnancy as they reduce placental perfusion by decreasing blood volume which can cause fetal death.

Spironolactone is an aldosterone antagonist. It is a synthetic steroid and structurally related to aldosterone.

Aldosterone enters the cell and binds to specific mineralocorticoid receptor (MR) in the cytoplasm of late distal tubule and CD cells (site 4). The hormone receptor complex (MR–AL) enters the cell nucleus, where it induces synthesis of aldosterone-induced proteins (AIPs). The net effect of AIPs is to retain sodium and excrete potassium ( Fig. 4.5 ).

The mechanism of action of spironolactone. MR, mineralocorticoid receptor; AL, aldosterone; AIPs, aldosterone-induced proteins.

Spironolactone competitively blocks the MR and prevents the formation of AIPs. Therefore, spironolactone promotes Na ⁺ excretion and K ⁺ retention. Spironolactone is most effective when circulating aldosterone levels are high. It also increases Ca ²⁺ excretion.

Both are directly acting potassium-sparing diuretics. They directly block Na ⁺ channels in the luminal membrane of the cells of late distal tubule and CD. The net effect of these drugs is to increase Na ⁺ excretion and retain potassium; hence, these are called potassium-sparing diuretics. They are administered orally. Amiloride inhibits H ⁺ secretion in CD – acidosis can occur. Both are low-efficacy diuretics. Amiloride is more potent and longer acting than triamterene. Triamterene is extensively metabolized while amiloride is excreted unchanged in urine.